ART812 is an orally bioavailable small-molecule inhibitor of DNA polymerase theta (Polθ) with an IC50 value of 7.6nM[1]. ART812 acts through an allosteric mechanism of inhibition, targeting the polymerase domain of Polθ, thereby eliciting synthetic lethality in tumor cells deficient in homologous recombination (HR) repair[2]. ART812 has demonstrated single-agent anti-tumor efficacy in preclinical studies against models of PARP inhibitor-resistant cancer[3-4].
In vitro, ART812 (100-500nM) treatment of HEK293 cells transfected with a microhomology-mediated end joining (MMEJ) reporter for 24 hours significantly inhibits TMEJ-mediated DNA repair activity[5].
In vivo, ART812 (100mg/kg) administered orally once daily (QD) to female SRG OncoRats bearing established MDA-MB-436 BRCA1 mutant, SHLD2 knockout tumor xenografts significantly inhibited tumor growth and was well-tolerated over a 76-day treatment period[1].
References:
[1] Zatreanu D, Robinson HMR, Alkhatib O, et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 2021 Jun 17;12(1):3636.
[2] Barszczewska-Pietraszek G, Drzewiecka M, Czarny P, et al. Polθ Inhibition: An Anticancer Therapy for HR-Deficient Tumours. Int J Mol Sci. 2022 Dec 24;24(1):319.
[3] Bazan Russo TD, Mujacic C, Di Giovanni E, et al. Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors. Cancer Gene Ther. 2024 Nov;31(11):1619-1631.
[4] Federica G, Michela C, Giovanna D. Targeting the DNA damage response in cancer. MedComm (2020). 2024 Oct 31;5(11):e788.
[5] Stockley ML, Ferdinand A, Benedetti G, et al. Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta. J Med Chem. 2022 Oct 27;65(20):13879-13891.
ART812是一种口服有效的DNA聚合酶θ（Polθ）小分子抑制剂，其IC50值为7.6nM[1]。ART812通过变构抑制方式作用于Polθ的聚合酶结构域，从而在同源重组修复（HR）缺陷的肿瘤细胞中引发合成致死效应[2]。ART812在临床前研究中显示出对PARP抑制剂耐药肿瘤模型的单药抗癌功效[3-4]。
在体外，ART812（100-500nM）处理转染microhomology-mediated end joining（MMEJ）的HEK293细胞24小时，可显著抑制MMEJ介导的DNA修复活性[5]。
在体内，ART812（100mg/kg）每日一次口服给药，用于处理携带MDA-MB-436 BRCA1突变且SHLD2敲除肿瘤的雌性Rats。ART812显著抑制了肿瘤生长，并在76天的治疗期间表现出良好的耐受性[1]。